EP1144395A1 - 2-oxy-4h-3,1-benzoxazine-4-ones destinees au traitement de l'obesite - Google Patents

2-oxy-4h-3,1-benzoxazine-4-ones destinees au traitement de l'obesite

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Publication number
EP1144395A1
EP1144395A1 EP00900081A EP00900081A EP1144395A1 EP 1144395 A1 EP1144395 A1 EP 1144395A1 EP 00900081 A EP00900081 A EP 00900081A EP 00900081 A EP00900081 A EP 00900081A EP 1144395 A1 EP1144395 A1 EP 1144395A1
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EP
European Patent Office
Prior art keywords
benzoxazin
heteroaryl
alkyl
compound
formula
Prior art date
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Application number
EP00900081A
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German (de)
English (en)
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EP1144395B1 (fr
Inventor
Harold Francis Hodson
Robert Cambridge Discovery Chemistry DOWNHAM
Timothy J. Cambridge Discovery Chem. Mitchell
Beverley Jane Carr
Christopher Robert Alizyme Therapeutics Ltd Dunk
Richard M. J. Alizyme TherapeuticLimited Palmer
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Norgine BV
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Alizyme Therapeutics Ltd
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Priority to SI200030674T priority Critical patent/SI1144395T1/xx
Publication of EP1144395A1 publication Critical patent/EP1144395A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
    • C07D265/26—Two oxygen atoms, e.g. isatoic anhydride
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/58—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring

Definitions

  • the present invention provides known and novel compounds, their use in the inhibition of an enzyme whose preferred mode of action is to catalyse the hydrolysis of an ester functionality (in vivo, as the enzyme naturally occurs) their use in medicine, and particularly in the prevention and/or treatment of obesity or an obesity- related disorder. Also provided are methods for the prevention and/or treatment of obesity or an obesity-related disorder and for promoting/aiding non-medical weight loss and the use of the compounds in the manufacture of a medicament for the aforementioned indications. In respect of novel compounds the invention also provides processes for their manufacture, compositions containing them and methods for manufacturing such compositions.
  • Obesity is now recognised by the medical profession as a metabolic disease. In the USA, it is estimated that 25% of the adult population is considered clinically obese (Body Mass Index>30). Obesity can be a debilitating condition which reduces the quality of life and increases the risk of related disorders such as diabetes, cardiovascular disease and hypertension. It has been estimated that $45 billion of US healthcare costs, or 8% per annum of total healthcare spend, is as a direct result of obesity. The traditional approaches to long term weight management such as diet and exercise have proved ineffective alone to control the spread of obesity. Today, more than ever, there is considerable interest in developing safe, effective drugs for the treatment of obesity.
  • A is -(CH 2 ) 5 - or
  • Orlistat has as its major active moiety a beta-lactone group that reacts to form an ester with the side chain hydroxyl group of serine 152 within the active site of pancreatic lipase.
  • each R' may be selected from a wide range of substituents; A is a bond or a Cj. 8 alkylene group; and R is ⁇ (except when A is a bond) phenyl, imidazolyl or C 3 _ 6 cycloalkyl each of which rings may be optionally substituted.
  • the R' groups are said to be preferably in the 5- and/or 7-positions of the ring.
  • a preferred value of the group A is lower alkylene having 1-4 carbon atoms. In the most preferred compounds A is ethylene.
  • the compounds are said to be useful as serine protease inhibitors and to treat physiologic conditions and disease states known to involve enzymes, or as contraceptives.
  • the specification describes various conditions and diseases involving enzymatic pathways, including inflammation, arthritis, tumor cell metastasis, pulmonary emphysema, mucocutaneous lymph node syndrome, adult respiratory distress syndrome and pancreatitis. It is also suggested that the compounds may have antiparasitic, anticoagulant and/or antiviral activity. Similar compounds are also described in US Patent No. 4,745,116.
  • R is inter alia an alkoxy group and R l5 R 2 , R 3 and R 4 (which may be the same or different) are selected from H, halogen, alkyl, alkenyl, aryl, hydroxyl, alkoxyl, amino, alkylamino, -COOR 5 and carbonyl functions.
  • R l5 R 2 , R 3 and R 4 (which may be the same or different) are selected from H, halogen, alkyl, alkenyl, aryl, hydroxyl, alkoxyl, amino, alkylamino, -COOR 5 and carbonyl functions.
  • the number of carbon atoms in the alkyl groups and moieties is not defined, but the specific examples are of lower alkyl and alkoxy groups e.g. R may be ethoxy.
  • East German Patent No. DD 246996 A 1 describes a process for preparing 2-alkoxy- and 2-aryloxy-3,l-benzoxazin-4-ones of the formula:
  • R' n represents one or more H atoms and/or other substituents such as alkyl, alkoxy, aralkyl, aryl, thiocyanato, mercapto, alkylthio, halogen or nitro
  • R 2 represents an alkyl, aralkyl or aryl residue.
  • the compounds are said to be useful as herbicides and fungicides and to have activity as inhibitors of chymotrypsin.
  • Specific examples of R 2 are ethyl, benzyl and phenyl.
  • the present invention provides the use of a compound comprising formula (I):
  • A is a 6-membered aromatic or heteroaromatic ring; and R 1 is a branched or unbranched alkyl (optionally interrupted by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aiyl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or a substituted derivative of any of the foregoing groups, wherein the substituents are one or more independently of halogen, alkyl, halosubstituted alkyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy, cyano, nitro, -C(O)R 4 , -CO 2 R 5 , -SOR 4 , -SO
  • R 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl, reduced heteroarylalkyl, -OR 6 , - NHCX 1 X 2 CO 2 R 6 or -NR 6 R 7 ;
  • R 5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl;
  • R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl or -(CH 2 )n(OR 5 )m wherein n is 1 to 12, preferably 2 to 10, wherein m is 1-3 and R 5 is most preferably C 2 -C ⁇ o alkyl; and
  • X and X are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl.
  • any alkyl, alkenyl and alkynyl groups and moieties may be straight chain (unbranched) or branched chain.
  • Straight chain alkyl, alkenyl and alkynyl groups or moieties may contain from 1 to 30 carbon atoms, eg. 1 to 25 carbon atoms, preferably 1 to 20 carbon atoms.
  • Branched chain alkyl, alkenyl and alkynyl groups or moieties may contain from 1 to 50 carbon atoms, preferably 1 to 30 carbon atoms.
  • R 1 , R 4 , R 5 , R 6 , R 7 , X 1 and X 2 are as defined below for formulae (II) and (Ila).
  • preferred values for R 4 , R 5 and R 6 are as defined for R 13 hereinbelow and preferred values for R 7 are as defined for R 14 hereinbelow.
  • 'reduced' in the context of 'reduced heteroaryl' and the like means fully or partially saturated.
  • Aryl groups include for example optionally substituted unsaturated monocyclic or bicyclic rings of up to 12 carbon atoms, such as phenyl and naphthyl, and partially saturated bicyclic rings such as tetrahydro-naphthyl.
  • substituents which may be present on an aryl group include one or more of halogen, amino, nitro, alkyl, haloalkyl, alkoxy, phenoxy and phenoxy substituted by one or more of halo, alkyl or alkoxy.
  • a heteroaryl group or moiety may be for example an optionally substituted 5- or 6- membered heterocyclic aromatic ring which may contain from 1 to 4 heteroatoms selected from O, N and S.
  • the heterocyclic ring may optionally be fused to a phenyl ring.
  • heteroaryl groups thus include furyl, thienyl, pyrrolyl, oxazolyl, oxazinyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl, pyrazolyl, indolyl, indazolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzoxazinyl, quinoxalinyl, quinolinyl, quinazolinyl, cinnolinyl, benzothiazolyl, pyridopyrrolyl.
  • Suitable substituents include one or more of halogen, oxo, amino, nitro, alkyl, haloalkyl, alkoxy, phenoxy and phenoxy substituted by one or more of halo, alkyl, haloalkyl or alkoxy.
  • a reduced heteroaryl group or moiety may be for example a fully or partially saturated derivative of the aforementioned heteroaryl groups.
  • Examples of reduced heteroaryl groups thus include pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl and piperidinyl.
  • the compounds of formula (I) are useful inhibitors of enzymes involved in the degradation of fats.
  • the first aspect of the invention provides the use of a compound of formula (I) as defined hereinabove, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, in the manufacture of a medicament for the control or treatment of obesity, or obesity-related disorders or for promoting non-medical weight loss.
  • a compound for use according to the first aspect of the invention is a compound of formula (II):
  • R .1 1 , ⁇ >4, ⁇ R,5 3 , R»6°, r R>7', v Xl 1 and X s are as defined above for formula (I);
  • R 8 , R 9 , R 10 , R 11 are each independently hydrogen, halo, hydroxy, amino, nitro, cyano,
  • R 12 Q where Q is O, CO, CONH, NHCO, S, SO, SO 2 , or SO 2 NH 2 and R 12 is hydrogen or a group R 1 as defined above,
  • R 1 is as defined above and R 2 is hydrogen or R 1 , with the proviso that any hetero atom substituent in R and/or R must be separated from the aromatic hetero atom substituent by at least two carbon atoms (preferably saturated).
  • Preferred values of R 1 , R 8 , R 9 , R 10 and R n are as defined below for compounds of formula (Ila).
  • a compound for use according to the first aspect of the invention comprises a compound of formula (II), or a pharmaceutically acceptable salt, ester, amide or prodrug therof; wherein:
  • R 1 is either a branched or unbranched alkyl group having up to 25, e.g. up to 20 carbon atoms, an aryl (e.g. optionally substituted phenyl or 2-naphthyl), an arylalkyl group wherein the alkyl moiety has up to 25, e.g.
  • aryl alkyl group or the aryl aryl group may be separated by a spacer, and where the spacer can be one or more of an ester, amide, O, CH 2 or a ketone and wherein any aryl group is preferably a phenyl, optionally substituted with alkyl, haloalkyl or halogen;
  • R is hydrogen or fluorine;
  • R >9 is lower branched or unbranched alkyl having 1 to 10 carbon atoms, preferably methyl; cyclic alkyl having 3 to 10 carbon atoms, preferably cyclopropyl; haloalkyl, preferably trifluoromethyl; or a halogen, most preferably chlorine or fluorine;
  • R 10 is hydrogen lower branched or unbranched alkyl having 1 to 10 carbon atoms, preferably methyl; cyclic alkyl having 3 to 10 carbon atoms, preferably cyclopropyl; haloalkyl, preferably trifluoromethyl; or a halogen, most preferably chlorine or fluorine;
  • R 11 is hydrogen lower branched or unbranched alkyl having 1 to 10 carbon atoms, preferably methyl, or halogen, preferably fluorine.
  • R 1 is an unbranched alkyl group, having 12, 14,15,16,17 or 18 carbon atoms in the alkyl chain.
  • R 9 may be methyl.
  • NR 13 R 14 OR 13 , SR 13 , -C(O)NR 13 R 14 , -NR 14 C(O)R 13 , halogen, cyano and nitro with the proviso that any hetero atom in R 1 must be separated from the exocyclic oxygen atom (or from any other heteroatom) by at least two carbon atoms (preferably saturated); or
  • R 13 and R 14 each independently represents hydrogen, Ci-ioalkyl
  • R 8a , R 9a , R 10a and R lla are each independently hydrogen, halo, hydroxy, amino, nitro, cyano, thiol, d-ioalkyl, d-ioalkoxy, d-* ⁇ ocycloalkyl, d-iocycloalkoxy, C(O)R 15 , C(O)NR 15 R 16 , S(O)R 15 or halod. 10 alkyl;
  • R 15 and R 16 each independently represent hydrogen or d-ioalkyl.
  • R la represents a group defined in (i) this is preferably a do- 25 e.g. a do- 20 branched or unbranched alkyl group, advantageously a C 12 - 18 e.g. a C 1 - ⁇ 8 branched or unbranched alkyl group, optionally interrupted by one or more oxygen atoms.
  • Optional substituents for said alkyl groups are preferably selected from one or more of aryl e.g. phenyl; heteroaryl e.g. thienyl; aryloxy, e.g. phenoxy; heteroaryloxy, e.g. benzoxazinyloxy; -CO 2 R 13 e.g.
  • R 13 and R 14 preferably each independently represent hydrogen or d- 6 alkyl.
  • R la represents a group defined by (ii) this is preferably a C 1 0- 25 e.g. a C 1 0- 2 0 branched or unbranched alkenyl or alkynyl group, advantageously a C 1 . 18 branched or unbranched alkenyl or alkynyl group.
  • Preferred optional substituents are those defined as preferred substituents in group (i).
  • R la represents a group defined by (iii) the C 1 -9 group preferably contains one or two oxygen atoms.
  • Preferred optional substituents are as defined above for groups (i) and (ii).
  • R la represents a group defined by (iv) preferred substituents are as defined above for groups (i) - (iii).
  • R la represents a group defined by (v) preferred substituents are selected from OR 17 , CO 2 R 13 , C(O)NR 13 R 14 , NR 14 C(O)R 13 and aryl C O alkyl.
  • the phenyl group R la and any additional phenyl group or moiety in the substituent may also be substituted by one or more of halogen, alkyl or haloalkyl.
  • R la represents a group defined by (vi) this is preferably selected from naphthyl, pyridyl, pyrrolyl and piperidinyl.
  • R la is preferably selected from groups (i) and (v) defined above.
  • R la is preferably d 0 - 20 branched or unbranched alkyl, optionally interrupted by one or two oxygen atoms and/or optionally substituted by one or more of aryl, eg. phenyl; aryloxy e.g. phenoxy wherein the phenyl moiety may be optionally substitued by alkyl, haloalkyl, halogen or phenoxy; heteroaryl, eg. thienyl; heteroaryloxy e.g. benzoxazinyloxy (which may optionally carry an oxo substituent); cyano, nitro, -CO 2 R 13 , -NR 13 R 14 , -CONR 13 R 14 , OH and halogen.
  • aryl eg. phenyl
  • aryloxy e.g. phenoxy wherein the phenyl moiety may be optionally substitued by alkyl, haloalkyl, halogen or phenoxy
  • R la is also advantageously phenyl substituted by one or more, but most preferably one, of OR 17 , -CO 2 R 13 , -C(O)NR 13 R 14 , NR 14 C(O)R 13 and aryl C,. ⁇ 0 alkyl.
  • R 13 and R 14 preferably each independently represent hydrogen or
  • R preferably represents phenyl, optionally substituted by alkyl, haloalkyl, halogen or phenoxy, wherein the phenyl moiety may also be optionally substituted by alkyl, haloalkyl or halogen.
  • R la is an unbranched alkyl chain having 14, 15, 16, 17 or 18 carbon atoms.
  • R 8a is preferably hydrogen or halogen eg. fluorine; most preferably hydrogen.
  • R 9a is preferably hydrogen or lower branched or unbranched alkyl having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, preferably methyl, cyclic alkyl having 3 to 6 carbon atoms, preferably cyclopropyl, haloC ⁇ -6alkyl, preferably trifluoromethyl or a halogen, preferably chlorine or fluorine;
  • R 10a is preferably hydrogen, lower branched or unbranched alkyl having 1 to 10 carbon atoms, preferably 1 -6 carbon atoms preferably methyl, cyclic alkyl having 3 to 6 carbon atoms preferably cyclopropyl, preferably trifluoromethyl or a halogen preferably chlorine or fluorine;
  • R l la is preferably hydrogen, halogen, eg. fluorine; or branched or unbranched alkyl having 1 to 10 carbon atoms, preferably 1-6 carbon atoms, eg. methyl.
  • R 8a may represent a hydrogen atom and R 9a , R 10a and R l la are as defined above.
  • each of R 8a and R l la represents a hydrogen atom
  • R 9a represents a substituent as defined above
  • R 10a represents a hydrogen atom or a substituent.
  • R 8a , R 9a and R 10a represent hydrogen and R Ua represents a substituent as defined above, eg. methyl.
  • R 8a , R 10a and R 1 la represents a hydrogen atom
  • R 9a represents a substituent as defined above, advantageously a C ⁇ - 6 alkyl group, especially methyl.
  • a further group of novel compounds within the scope of ' formula (II) is that wherein R 1 is as defined for formula (II) and at least one of R 8 , R 9 , R 10 and R 11 represents a
  • R 9 or R 10 represents a C 8- ⁇ o alkyl group and the remaining substituents on the benzene ring are all hydrogen.
  • Examples of pharmaceutically acceptable salts of the above compounds include those derived from organic acids such as methanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid, mineral acids such as hydrochloric and sulphuric acid and the like, giving methanesulphonate, benzenesulphonate, p-toluenesulphonate, hydrochloride and sulphate, and the like, respectively or those derived from bases such as organic and inorganic bases.
  • suitable inorganic bases for the formation of salts of compounds for this invention include the hydroxides, carbonates, and bicarbonates of ammonia, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc and the like.
  • Salts can also be formed with suitable organic bases.
  • bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases which are nontoxic and strong enough to form salts.
  • organic bases are already well known in the art and may include amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; N-methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine;
  • N-benzylphenethylamine tris(hydroxymethyl) aminomethane; and the like.
  • Salts may be prepared in a conventional manner using methods well known in the art. Acid addition salts of said basic compounds may be prepared by dissolving the free base compounds according to the first or second aspects of the invention in aqueous or aqueous alcohol solution or other suitable solvents containing the required acid. Where a compound of formula (I) contains an acidic function a base salt of said compound may be prepared by reacting said compound with a suitable base. The acid or base salt may separate directly or can be obtained by concentrating the solution eg. by evaporation. The compounds of this invention may also exist in solvated or hydrated forms.
  • a prodrug is commonly described as an inactive or protected derivative of an active ingredient or a drug which is converted to the active ingredient or drug in the body.
  • Representative compounds according to the first and/or second aspects of the invention are those which include:
  • Preferred compounds of formula (II) listed in Table 1 include compounds numbers 4, 5, 8, 10, 11, 12, 13, 14, 21, 26, 27, 28, 30, 32, 33, 34, 35 and 78.
  • Preferred compounds of formula (Ila) listed in Table 1 include compounds numbers
  • Preferred compounds of the invention listed above extend to the tautomers thereof, as well as (but not limited to) pharmaceutically acceptable salts, esters, amides or prodrugs thereof or a derivative optionally with one or more lipid groups (natural or synthetic) attached.
  • a third aspect of the invention provides a process for the manufacture of any one or more of the novel compounds or derivatives according to the first or second aspects of the invention.
  • the present invention provides a process for the preparation of a novel compound of formula (II) in particular a compound of formula (Ila) which process comprises:
  • R , ⁇ and R , 8 - ⁇ R> l l are as hereinbefore defined and R is hydrogen or C h alky! or:
  • Process (A) may be effected by reacting a compound of formula (IN) with a chloroformate of formula (V).
  • the process is preferably carried out under basic conditions, e.g. using pyridine.
  • the reaction may be cooled to avoid overheating.
  • the resulting carbamate intermediate is then cyclised by reaction with excess chloroformate or by addition of another cyclisation reagent, which promotes ring closure.
  • Suitable cyclisation reagents include for example, methyl chloroformate, carbonyl diimidazole, acetic anhydride, phosgene, pxalyl chloride, thionyl chloride or a peptide coupling agent such as dicyclohexyl carbodiimide (DCC).
  • DCC dicyclohexyl carbodiimide
  • the cyclisation reagent is preferably phosgene, triphosgene or thionyl chloride. It will be understood by those skilled in the art that when a chloroformate is used to effect the cyclisation, this may be provided by employing an excess of the compound of formula (V). Preferably, however, a low molecular weight chloroformate is employed, on grounds of cost and ease of removing the resulting alcohol.
  • Compounds of formula (V) for use in the process (A) may be prepared by standard methods well known in the art, e.g. by reaction of the corresponding alcohol R J OH with phosgene in a solvent such as toluene.
  • the product may be isolated in conventional manner by removal of solvent and volatile by-products.
  • Process (B) may be effected by reaction of a compound (NI) wherein R 18 is hydrogen, in the presence of a cyclisation reagent, e.g. an alkyl chloroformate, for example as described for process (A).
  • a compound (NI) may be cyclised by treatment with a dehydrating agent such as concentrated sulphuric acid.
  • R is an alkyl group
  • R is an alkyl group
  • an ester corresponding to formula (IN) with e.g. phosgene and a base such as pyridine to afford the corresponding isocyanate, followed by treatment with an alcohol R ⁇ H.
  • the ester i.e. where R 18 is alkyl
  • R 18 H
  • lithium hydroxide e.g. aqueous tetrahydrofuran or aqueous dioxane.
  • Process (A) also proceeds via an intermediate of formula (VI) and is hence a variant of process (B).
  • Process (C) may be effected by reacting a compound of formula (Nil) with an alcohol R ! OH in the presence of a base, e.g. Hunig's base (diisopropylethylamine).
  • a compound of formula (Nil) may be prepared from the corresponding anhydride of formula (DC)
  • the anhydride of formula (DC) may itself be obtained by cyclisation of a compound of formula (IN), for example using phosgene or a synthetic equivalent .
  • reduction of an alkenyl or alkynyl group may be effected for example by catalytic hydrogenation using e.g. 10% palladium on charcoal in an alcoholic solvent, such as ethanol, under 1 atmosphere of hydrogen gas.
  • Alkylation according to process (D)(ii) may be effected using a Stille or other palladium catalysed cross-coupling process, using e.g. tetra-alkyl tin such as tetramethyl tin and PhCH 2 Pd(PPh 3 ) 2 Cl in HMPA at elevated temperature e.g. 50-
  • halides or pseudohalides e.g. triflates may be employed as starting materials.
  • a fourth aspect of the invention is a compound according to the first and second aspects of the invention (i.e. compounds of formulae (I), (II) and (Ila)), for use in medicine. Preferred features of the first and second aspects of the invention also apply to the fourth aspect. Further details of the fourth aspect of the invention are set out in the text which follows.
  • a fifth aspect of the invention relates to a compound according to the first and/or second aspects of the invention for use in the inhibition of an enzyme whose preferred mode of action is to catalyse the hydrolysis of an ester functionality.
  • an enzyme whose preferred mode of action is to catalyse the hydrolysis of an ester functionality.
  • Such an enzyme is one which catalyses the breakdown of a substrate containing an ester functionality by the addition of water, resulting in the cleavage of a chemical bond.
  • Such enzymes are involved in key processes in the body.
  • Enzymes according to this invention include lipases (hydrolyse fatty acid esters), esterases (hydrolyse esters) and phosphatases (hydrolyse phosphate esters).
  • the enzyme is preferably a lipase.
  • Lipases include pancreatic lipase, gastric lipase, lipoprotein lipase, lingual lipase, adipose tissue lipase, hormone sensitive lipase, phospholipase Al, A2, B, C, D etc., hepatic lipase, and other triacyl, diacyl and monoacylglycerol lipases in the mammalian body. Many similar such lipases are also known in plants, fungi and microorganisms.
  • Esterase enzymes include pig liver esterase, cholesteryl esterase, retinyl esterase, l-alkyl-2- acetylglycerophosphocholine esterase, carboxylic ester hydrolases, and cholesterol esterase.
  • Phosphatase enzymes include serine/threonine phosphatases PP1, PP2 and PP3, phosphoprotein phosphatase, myosin-light-chain phosphatase, protein phosphoprotein 2C, and protein tyrosine phosphatase.
  • Compounds according to the invention for use in medicine, are primarily for use in relation to the prevention and/or treatment of a medical condition such as obesity, hyperlipaemia, hyperlipidaemia and related diseases such as hyperglycaemia (type II diabetes), hypertension, cardiovascular disease, stroke, gastrointestinal disease and gastrointestinal conditions.
  • a medical condition such as obesity, hyperlipaemia, hyperlipidaemia and related diseases such as hyperglycaemia (type II diabetes), hypertension, cardiovascular disease, stroke, gastrointestinal disease and gastrointestinal conditions.
  • Compounds according to the first and second aspect of the invention are useful in these and other conditions due to their ability to inhibit an enzyme whose preferred mode of action is to catalyse the hydrolysis of an ester functionality (in vivo, as the enzyme naturally occurs).
  • the invention also relates to non-medical weight loss, such as cosmetic weight loss and includes improving bodily appearance in general.
  • prevention and/or treatment of any disorder means any effect which mitigates any damage or any medical disorder, to any extent, and includes prevention and treatment themselves.
  • treatment means any amelioration of disorder, disease, syndrome, condition, pain or a combination of two or more thereof.
  • an important application of the invention is in relation to weight loss (of all kinds as described above) in humans.
  • the invention applies to medical and non-medical weight loss in any animal whose metabolism of fat and fat derivatives involves an enzyme whose preferred mode of action is to catalyse the hydrolysis of an ester functionality (in vivo, as the enzyme naturally occurs).
  • the invention has veterinary application and is particularly useful in relation to medical and non-medical weight loss in companion animals such as pet cats and dogs as well as in animals which provide meat for human consumption.
  • the application of the present invention is to reduce fat content in order to provide a leaner meat product.
  • the compounds may be useful in reducing levels of toxins (e.g. dioxins and PCBs) stored in body fat. Without wishing to be bound by theory, it is believed that increasing the amount of undigested fat passing through the body enhances diffusion of toxins from fat stored in the body into fats in the blood, and thence into the intestine.
  • the fifth aspect of the invention has important applications. It includes test and diagnostic methods and the control and inhibition of unwanted enzymes, preferably lipases, in any process or in any product.
  • the processes or products, which preferably involve a lipase include: processing of agricultural commodities (e.g. oilseeds), recovery and isolation of enzymes from biotechnological processes (e.g.
  • the invention also relates to these products and processes, e.g.
  • a foodstuff which comprises a compound according to the first aspect of the invention, in particular foodstuffs which have a high fat content such as cakes, biscuits, pastry-products and the like and chocolate products.
  • the preferred features of the fifth aspect of the invention including an enzyme whose preferred mode of action is to catalyse the hydrolysis of an ester functionality (in vivo, as the enzyme naturally occurs) are as discussed for the previous aspects of the invention.
  • a sixth aspect of the invention provides a composition comprising a novel compound according to the first or second aspect of the invention, in combination with a pharmaceutically acceptable carrier or diluent.
  • suitable carriers and/or diluents are well known in the art and include pharmaceutical grade starch, mannitol, lactose, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, (or other sugar), magnesium carbonate, gelatin, oil, alcohol, detergents, emulsifiers or water
  • the composition may be a mixed preparation of a composition or may be a combined preparation for simultaneous, separate or sequential use (including administration).
  • the compounds according to the invention for use in the aforementioned indications may be administered by any convenient method, for example by oral (including by inhalation), parenteral, mucosal (e.g. buccal, sublingual, nasal), rectal or transdermal administration and the compositions adapted accordingly.
  • the compounds can be formulated as liquids or solids, for example solutions, syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable aqueous or non-aqueous liquid carrier(s) for example water, ethanol, glycerine, polyethylene glycol or an oil.
  • a suitable aqueous or non-aqueous liquid carrier(s) for example water, ethanol, glycerine, polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and microcrystalline cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • powders, granules or pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the alimentary tract, for example by an outer coating of the formulation on a tablet or capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous or non-aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal or oral administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser, it will contain a pharmaceutically acceptable propellant.
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • compositions for rectal or vaginal administration are conveniently in the form of suppositories (containing a conventional suppository base such as cocoa butter), pessaries, vaginal tabs, foams or enemas.
  • compositions suitable for transdermal administration include ointments, gels, patches and injections including powder injections.
  • the composition is in unit dose form such as a tablet, capsule or ampoule.
  • compositions of the sixth aspect of the invention are useful in the prevention and/or treatment of obesity, obesity-related disorder, other medical weight loss and non-medical related weight loss.
  • Preferred features of this aspect of the invention are as described above for the first to fifth aspects of the invention.
  • a seventh aspect of the invention provides a process for the manufacture of a composition according to the sixth aspect of the invention.
  • the manufacture can be carried out by standard techniques well known in the art and involves combining a compound according to the first or second aspect of the invention and the pharmaceutically acceptable carrier or diluent.
  • the composition may be in any form including a tablet, a liquid, a capsule, and a powder or in the form of a food product, e.g. a functional food. In the latter case the food product itself may act as the pharmaceutically acceptable carrier.
  • An eighth aspect of the invention provides a method for the prevention and/or treatment of obesity or an obesity-related disorder, the method comprising the administration of a compound according to the first or second aspect of the invention, preferably in combination with a pharmaceutically acceptable carrier or diluent (as per the sixth aspect of the invention).
  • Obesity-related disorders include hyperlipeamia, hyperlipideamia, hyperglycaemia, hypertension, cardiovascular disease, stroke, gastrointestinal disease and gastrointestinal conditions.
  • the compound or composition is preferably administered to a patient in need thereof and in a quantity sufficient to prevent and/or treat the symptoms of the condition, disorder or disease.
  • the administration of a compound or composition has a dosage regime which will ultimately be determined by the attending physician and will take into consideration such factors such as the compound being used, animal type, age, weight, severity of symptoms, method of administration, adverse reactions and/or other contraindications.
  • Specific defined dosage ranges can be determined by standard design clinical trials with patient progress and recovery being fully monitored. Such trials may use an escalating dose design using a low percentage of the maximum tolerated dose in animals as the starting dose in man.
  • the physiologically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 2000 mg, preferably between 30 mg and 1000 mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0J mg and 100 mg, preferably between 0J mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • a ninth aspect of the invention provides a cosmetic method (non-therapeutic) for maintaining a given weight, or for cosmetic weight loss, the method comprising the administration of a compound according to the first or second aspect of the invention, preferably in combination with a pharmaceutically acceptable carrier or diluent (as per the sixth aspect of the invention).
  • the compound or composition is preferably administered to a subject in need or in desideratum thereof and in a quantity sufficient to maintain a given weight or for cosmetic weight loss.
  • the eighth and ninth aspects of the invention relate to methods which are applicable to humans and other animals, in particular companion animals (such as dogs and cats) and other animals which provide meat for human consumption, such as cattle, pigs and sheep (all of any age).
  • Test Compounds The benzoxazinone compounds used in the following tests are identified by the reference number assigned in Table 1 hereinbefore.
  • the inhibitory activity of the selected compounds to pancreatic lipase was measured in the following assay available from Sigma Ltd (Lipase-PSTM , catalog number 805-A):
  • the glycerol released from the action of pancreatic and monoglyceride lipase was oxidised to release H 2 O 2 .
  • the peroxidase reaction step then produces a quinine dye which is pink in colour and absorbs light at a wavelength of 550 nm.
  • DMSO dimethyl sulphoxide
  • the inhibitory activity of the selected .compounds to pancreatic lipase was measured in the assay described in Pasquier et al ; 1996, Vol 7, Nutritional Biochemistry, 293-302.
  • Porcine trypsin (Boehringer) was dissolved at a concentration of 1 mg/ml in 100 mM
  • MOPS 3-[N-Morpholino]propanesulphonic acid pH 1.3 containing 2 mM CaCl 2 . Prior to use, the enzyme was diluted 500 times to give a final concentration of 2 ⁇ g/mk
  • DMSO Dimethylsulphoxide
  • the assay was set up in triplicate in a 96 well ELISA plate. 10 ⁇ l 2 ⁇ g/ml trypsin, 26 ⁇ l diluted inhibitor and 190 ⁇ l substrate were added sequentially. The plates were then incubated at 37 °C in a BioRad Benchmark Microplate Reader. The rate of release of -nitroaniline was measured at 405 nM over 10 minutes relative to that of the enzyme without inhibitor.
  • Bovine Chymotrypsin (Sigma Type 11 Cat. No. C4129) was dissolved at a concentration of 1 mg/ml in lOOmM Tris pH 7.8. Prior to use, the enzyme was diluted 20 fold immediately before use, with the same buffer.
  • the assay was set up in triplicate in a 96 well ELISA plate. 10 ⁇ l 50 ⁇ g/ml chymotrypsin, 50 ⁇ l diluted inhibitor and 190 ⁇ l substrate were added sequentially.
  • the selectivity of compound 18 towards human pancreatic lipase, trypsin and chymotrypsin was measured in the assays described above.
  • the inhibitory activity of compound 18 towards lipase was assessed in the quinine diimine dye colorimetric assay.
  • compound 18 had inhibited 98.7% of the pancreatic lipase activity but only 4% of the trypsin activity and 12.5% of the chymotrypsin activity. Thus compound 18 is a highly selective lipase inhibitor.
  • Compound 18 was assayed in a mouse model as described by Isler et al., British Journal of Nutrition, 1995, 73:851-862 and was found to be a potent lipase inhibitor.
  • the substrate (1.7g, 5.4mmol), copper (I) cyanide (0.533g, 5.9mmol) and pyridine (20ml) were refluxed at 150°C for 2 days. Concentration in vacuo and purification by flash chromatography (10% to 20% EtOAc/hexane) gave the desired material as a brown oil (739mg, 2.8mmol)
  • the substrate (694mg, 2.7mmol) was heated at 150°C in a mixture of water (2ml), AcOH (1ml) and sulfuric acid (1ml) for 2 days.
  • the mixture was extracted with ethyl acetate, the organic phase being washed with water (x 2), dried (Na 2 SO 4 ) and concentrated to give the desired material (744mg, 2Jmmol).
  • the starting material (744mg, 2.7mmol) was dissolved in ethanol (10ml) and to this was added a slurry of 10% palladium on charcoal (40mg) in ethanol (4ml). The flask was flushed with nitrogen then hydrogen (1 atm) after which stirring was maintained overnight. Further portions of catalyst (5mg and 25mg) were added, the reaction being complete after a further 24h. The reaction mixture was filtered through celite, thoroughly rinsing with methanol and ethyl acetate.
  • Chloral hydrate (3.97g, 24mmol) was dissolved in water (50ml). To this solution was added, sequentially, anhydrous sodium sulfate (5.5g, 39mmol), 4-octylaniline (5ml, 22mmol), water (15ml), concentrated hydrochloric acid (2.3ml) -and an aqueous solution of hydroxylamine hydrochloride (4.5g in 22ml, 65mmol). The heterogeneous mixture was heated to 95°C for 2 h, then 110°C for a further 1 h. The reaction mixture was cooled to room temperature, the brown precipitate filtered and washed with water.
  • the oxime (1.8g, 6.5mmol) was added to a mixture of cone, sulfuric acid (13ml) and water (1ml) at 60°C over the course of 15 min. The mixture was then heated to 80°C for 2h then stood at room temperature overnight. This was then extracted with ethyl acetate (x3), the combined organic layers being washed with saturated aqueous sodium bicarbonate and water until the washings were neutral. The organic phase was dried (MgSO 4 ) and concentrated to give the isatin as a red solid (1.5g, 5.8mmol), which was used without further purification.
  • 2-Amino-5-methylbenzoic acid (100 mg, 0.64 mmol, 0.2-eq.) was dissolved in pyridine (10 ml). The chloroformate solution was added dropwise by syringe and the mixture stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (100 ml) and washed with 10% aqueous citric acid (100 ml, x2), saturated sodium bicarbonate solution (100 ml, x2), water (100 ml) and saturated brine (100 ml).
  • 1-Hexadecanol (5.01 g, 20.6 mmol, 1 eq.) was dissolved in THF (10 ml) under nitrogen and added to a 20% solution of phosgene in toluene (29 ml, 62.5 mmol, 3 eq.). The mixture was stirred at room temperature for 2 hours, then the apparatus was purged with nitrogen (scrubbed on exit with 5M sodium hydroxide) to remove excess phosgene.

Abstract

L'invention concerne l'utilisation d'un composé de formule (I) ou d'un sel, d'un ester, d'un amide ou d'un promédicament dudit composé, pour inhiber une enzyme dont le mode d'action préféré est de catalyser l'hydrolyse d'une fonctionnalité ester, par exemple pour la régulation et l'inhibition des enzymes indésirables dans les produits et les processus. Ces composés sont également utiles en médecine, par exemple pour le traitement de l'obésité et des pathologies voisines. L'invention concerne également des composés de formule (I), des procédés permettant de les préparer et des compositions pharmaceutiques les contenant. Dans la formule (I), A est un noyau aromatique ou hétéro-aromatique à 6 éléments; et R1 est alkyle ramifié ou non ramifié (éventuellement interrompu par un ou plusieurs atomes d'oxygène), alcényle, alcinyle, cycloalkyle, cycloalcényle, aryle, arylalkyle, arylalkyle réduit, arylalcényle, hétéroaryle, hétéro-arylalkyle, hétéro-arylalcényle, aryle réduit, hétéro-aryle réduit, hétéro-arylalkyle réduit, ou un dérivé substitué de l'un des groupes ci-dessus.
EP00900081A 1999-01-08 2000-01-06 2-amino-benzoxazinones destinees au traitement de l'obesite Expired - Lifetime EP1144395B1 (fr)

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GBGB9900416.0A GB9900416D0 (en) 1999-01-08 1999-01-08 Inhibitors
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ES2240051T3 (es) 2005-10-16
NO20013380L (no) 2001-09-07
US20030191123A1 (en) 2003-10-09
CN1354747A (zh) 2002-06-19
US20030013707A1 (en) 2003-01-16
NZ512739A (en) 2003-10-31
PL350412A1 (en) 2002-12-02
AR022203A1 (es) 2002-09-04
CA2359987C (fr) 2008-03-25
EP1144395B1 (fr) 2005-04-20
NO20013380D0 (no) 2001-07-06
AU1884500A (en) 2000-07-24
AU770342B2 (en) 2004-02-19
US6656934B2 (en) 2003-12-02
HK1047284A1 (en) 2003-02-14
US7776853B2 (en) 2010-08-17
CN100480245C (zh) 2009-04-22
HUP0104909A2 (hu) 2002-04-29
CA2359987A1 (fr) 2000-07-13
KR20010108073A (ko) 2001-12-07
DK1144395T3 (da) 2005-08-15
JP2002534419A (ja) 2002-10-15
GB9900416D0 (en) 1999-02-24
RU2244711C2 (ru) 2005-01-20
WO2000040569A1 (fr) 2000-07-13
PT1144395E (pt) 2005-08-31
NO321058B1 (no) 2006-03-06
HUP0104909A3 (en) 2004-11-29
DE60019556D1 (de) 2005-05-25
MY129247A (en) 2007-03-30
WO2000040569A9 (fr) 2002-02-28
KR100615914B1 (ko) 2006-08-28
DE60019556T2 (de) 2006-02-23
ATE293610T1 (de) 2005-05-15

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